Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.fals

Supplementary Material for: Migratory Behavior of Presumptive Interneurons Is Affected by AMPA Receptor Activation in Slice Cultures of Embryonic Mouse Neocortex

It has been reported that functional α-amino-3-hydroxy-5-methyl-isoxazolpro-prionic acid (AMPA) receptors permeable to calcium are already expressed by tangentially migrating prospective interneurons in the developing rodent cerebral cortex. However, the role of these receptors is not yet fully understood. To examine the effect of activation of AMPA receptors on tangential migration, we exposed migrating prospective interneurons derived from the medial ganglionic eminence (MGE) to AMPA in slice cultures and performed time lapse imaging. In the neocortex, a subpopulation of MGE-derived cells stopped migration or changed the direction of migration in response to AMPA in a dose-dependent manner. In contrast, neither MGE-derived cells migrating in the subcortical territory nor radially migrating cells in the neocortex were affected by exposure to AMPA. Transfection of dominant-negative AMPA receptor subunit GluR1 to the tangentially migrating cells prevented the effects of AMPA on migration. This study provides evidence that the activation of AMPA receptors can directly affect tangential migration in the neocortical part of telencephalic slice cultures

Australasian Gastrointestinal Pathology Society (AGPS) consensus guidelines for universal defective mismatch repair testing in colorectal carcinoma

Lynch syndrome is the most common hereditary form of colorectal carcinoma caused by a constitutional pathogenic mutation in a DNA mismatch repair gene. Identifying Lynch syndrome is essential to initiate intensive surveillance program for the patient and affected relatives. On behalf of the Australasian Gastrointestinal Pathology Society (AGPS), we present in this manuscript consensus guidelines for Lynch syndrome screening in patients with colorectal carcinoma. The goal of this consensus document is to provide recommendations to pathologists for diagnosis of Lynch syndrome with discussion of the benefits and limitations of each test. Universal screening for defective mismatch repair is recommended, in agreement with the recent endorsement of universal testing by the National Health and Medical Research Council in Australia and the New Zealand Ministry of Health. The value of evaluating defective mismatch repair is acknowledged not only for Lynch syndrome screening but also for therapeutic decision information in patient management. AGPS advocates appropriate government funding for the molecular tests necessary for Lynch syndrome screening (BRAF mutation, MLH1 methylation testing)

Immediate synergistic effect of a trunk orthosis with joints providing resistive force and an ankle–foot orthosis on hemiplegic gait

Junji Katsuhira,1,2 Sumiko Yamamoto,3 Nodoka Machida,4 Yuji Ohmura,5 Masako Fuchi,6 Mizuho Ohta,7 Setsuro Ibayashi,7 Arito Yozu,8 Ko Matsudaira2 1Department of Prosthetics and Orthotics and Assistive Technology, Faculty of Medical Technology, Niigata University of Health and Welfare, Niigata, 2Department of Medical Research and Management for Musculoskeletal Pain, 22nd Century Medical and Research Center, The University of Tokyo, Tokyo, 3Graduate School of International University of Health and Welfare, Tokyo, 4International University of Health and Welfare, School of Health Sciences at Narita, Department of Physical Therapy, Chiba, 5International University of Health and Welfare, School of Health Sciences at Odawara, Department of Physical Therapy, Kanagawa, 6Department of Occupational Therapy, Kyusyu Nutrition Welfare University, Fukuoka, 7Seiai Rehabilitation Hospital, Fukuoka, 8Center for Medical Sciences, Ibaraki Prefectural University of Health Science, Ibaraki, Japan Purpose: The synergistic effects of a trunk orthosis and an ankle–foot orthosis (AFO) in stroke patients with a hemiplegic gait are unclear. We previously developed a trunk orthosis with joints providing resistive force (TORF) to modify malalignment of the trunk and pelvis and confirmed its positive effects in stroke patients during level walking without an AFO. The aim of the present study was to determine if this trunk orthosis and an AFO have synergistic effects during level walking in community-dwelling patients with chronic stroke. Methods: Twenty-eight community-dwelling stroke patients performed level walking at a self-selected speed with an AFO and again while wearing a TORF (TORF group) or a corset (control group). Spatiotemporal, kinematic, and kinetic data were recorded using a three-dimensional motion analysis system. Results: When compared with the control group, the TORF group showed significant increases in walking speed, number of steps on the paretic leg per minute, and peak ankle plantar flexion moment during the single stance phase. Conclusion: The TORF increased the ankle joint plantar flexion moment at the end of the single stance phase during level walking in stroke patients, leading to an increase in their gait speed because of the modified trunk and pelvis alignment. Keywords: biomechanics, orthosis, gait, stroke, joint moment, motion analysi